Project Summary In addition to seizures, temporal lobe epilepsy (TLE) patients suffer from a range of comorbidities, including cognitive decline. TLE itself afflicts approximately 1.7 per 1000 people, and tragically, one-third of this substantial patient population experiences uncontrolled seizures with current pharmacological treatment options. Longitudinal evidence suggests that lack of seizure control is a leading predictor of cognitive deterioration in patients with TLE. Yet the impact of seizure intervention on cognitive outcomes ? and their mutual relationship to anatomical changes in TLE ? remains to be investigated. Without this knowledge, the ability to implement therapies addressing TLE-associated cognitive decline will be greatly inhibited. Identifying the role of recurrent seizures and important neuronal populations will inform future clinical therapies aimed at treating cognitive comorbidities. Our preliminary data demonstrate specific and robust memory deficits in conjunction with abnormal anatomical phenotypes in epileptic mice. These results are in general agreement with observations in human TLE patients that report anatomical pathologies and memory deficits. Other studies examining patients that achieve seizure remission report stabilized or improved cognitive functioning. This suggests that stopping seizures will lead to positive cognitive outcomes. Therefore, we hypothesize that chronic on-demand optogenetic intervention can alleviate cognitive deficits in epileptic mice. We will address this hypothesis through the following Specific Aims: 1A) determine the relative effectiveness of hippocampal, lateral cerebellar, and vermal targeting at cognitive rescue in epileptic mice; 1B) compare strategies of chronic optogenetic seizure intervention at cognitive rescue; and 2) determine the relationship between neuropathologies of TLE, seizure intervention, and cognitive impairment. We will utilize in the intrahippocampal kainic acid (IHKA) mouse model of TLE to induce spontaneous seizures. In these mice, we will implement an optogenetic seizure intervention system to specifically control the pattern and location of seizure intervention. The information obtained from this project will inform the controversy of whether or not spontaneous seizures in chronic epilepsy accumulate damage and result in cognitive decline. Furthermore, these results will identify key elements of seizure intervention and neuropathologies that correlate with cognitive outcomes, providing direction for future investigations to treat this debilitating disorder.